The SOS1i::KRAS inhibitor BI 1701963 is the first direct RAS signaling modifier to enter phase I clinical trials both as a monotherapy as well as in combination. SOS1::KRAS inhibitors exhibit activity against a broad spectrum of KRAS alleles, including the major G12D/V/C and G13D oncoproteins, while sparing the interaction of KRAS with SOS2. Here, we present pre-clinical data showing enhanced pathway modulation and synergistic anti-tumor effects following vertical pathway inhibition of BI 1701963 in combination with mitogen-activated protein kinase inhibitors (MEKi; trametinib and BI 3011441) or KRAS G12C inhibitors (MRTX849 and BI 1823911). Furthermore, SOS1::KRAS inhibitor treatment sensitizes tumor cells to increased DNA damage in combination with irinotecan. Our results highlight the suitability of SOS1::KRAS inhibitors as a backbone in combination therapies targeting KRAS-dependent tumors. Pre-clinical combination data supported the start of multiple phase I trials investigating the safety, tolerability, recommended dose and preliminary efficacy of BI 1701963 alone and in combination with other anti-cancer agents. Combination trials of BI 1701963 with MEKi include cohorts of patients with KRAS mutant solid tumors, such as non-small cell lung cancer (NSCLC), colorectal cancer (CRC), cholangiocarcinoma and pancreatic adenocarcinoma. Trials exploring the combination of BI 1701963 with irreversible KRAS G12C inhibitors (MRTX849 and BI 1823911) will include cohorts of patients with KRAS G12C mutant NSCLC and CRC. In a further study, the combination of BI 1701963 with irinotecan is being evaluated in patients with KRAS mutant CRC. Primary endpoints include dose-limiting toxicities, treatment-emergent or -related adverse events. Secondary endpoints include pharmacokinetic and pharmacodynamic properties of combination regimens and preliminary efficacy.
Citation Format: Marco H. Hofmann, Hengyu Lu, Ulrich Duenzinger, Daniel Gerlach, Francesca Trapani, Annette A. Machado, Joseph R. Daniele, Irene Waizenegger, Michael Gmachl, Dorothea Rudolph, Christopher P. Vellano, Marcelo Marotti, Vitomir Vucenovic, Timothy P. Heffernan, Joseph R. Marszalek, Mark P. Petronczki, Norbert Kraut. Trial in Process: Phase 1 studies of BI 1701963, a SOS1::KRAS Inhibitor, in combination with MEK inhibitors, irreversible KRASG12C inhibitors or irinotecan. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT210.